This application claims priority of German 199,3.5771.4 filed on Jul. 23, 1999.
The invention relates to new vitamin D derivatives of general formula I 
process for their production, intermediate products of the process as well as the use for the production of pharmaceutical agents.
Natural vitamins D2 and D3 are inherently biologically inactive and are converted into biologically active metabolites [1xcex1, 25-dihydroxy vitamin D3 (calcitriol) or -D2] only after hydroxylation at C-atom 25 in the liver and at C-atom 1 in the kidney. The action of the active metabolites involves the regulation of the calcium and phosphate concentration in the serum; they counteract a dropping of the calcium concentration in the serum by increasing the calcium absorption in the intestine and under certain circumstances promoting calcium mobilization from the bones. Table 1 shows the structure of some known vitamin D derivatives:
In addition to their pronounced effect on the calcium and phosphate metabolism, the active metabolites of vitamin D2 and vitamin D3 and their synthetic derivatives have a proliferation-inhibiting and differentiation-stimulating action on tumor cells and normal cells, such as, for example, skin cells. In addition, a pronounced effect on cells of the immune system (inhibiting of proliferation and interleukin-2-synthesis of lymphocytes, increase of cytotoxicity and phagocytosis in vitro of monocytes) has been found, which manifests itself in an immunomodulatory action. Finally, because of a stimulating action on bone-forming cells, an increased formation of bone in normal and osteoporotic rats is found [R. Bouillon et al. xe2x80x9cShort Term Course of 1,25(OH)2D3 Stimulates Osteoblasts But Not Osteoclasts,xe2x80x9d Calc. Tissue Int. 49, 168 (1991)]. All actions are mediated by binding to the vitamin D receptor. Because of the binding, the activity of specific genes is regulated.
When using biologically active metabolites of vitamins D2 and D3, a toxic effect on the calcium metabolism is produced (hypercalcemia).
By structural manipulations of the side chain, therapeutically usable effectiveness can be separated from undesirable hypercalcemic activity. A suitable structural variant is the introduction of a 24-hydroxy group.
1xcex1-Cholecalciferols that are hydroxylated in 24-position are already described in DE 25 26 981. They have a lower toxicity than the corresponding non-hydroxylated 1xcex1-cholecalciferol. Further, 24-hydroxy derivatives are described in the following patent applications: DE 39 33 034, DE 40 03 854, DE 40 34 730 (?), EP 0 421 561, EP 0 441 467, WO 87/00834, and WO 91/12238.
Finally, 25-carboxylic acid derivatives of calcitriol that are hydroxylated at C-24 are described in WO 94/07853, and said derivatives exhibit a more advantageous spectrum of action than calcitriol. The equivalent is also true for new vitamin D derivatives with other substituents at C-25 (WO 97/00242). While the ability to trigger a hypercalcemia is considerably weakened, proliferation-inhibiting and differentiation-stimulating actions are maintained. Generally, however, the introduction of the 24-hydroxyl group results in metabolic destabilization of the derivatives. For this reason, these compounds are only conditionally suitable for systemic administration.
There is therefore a need for new vitamin D derivatives that have as advantageous or improved a spectrum of action as the compounds that are described in the prior art (especially WO 94/07853 and WO 97/00242), but that are better suited for systemic administration owing to their higher metabolic stability.
The object of this patent application is therefore to make available such vitamin D derivatives. This object is achieved by the compounds that are disclosed in the claims.
This invention therefore relates to vitamin D derivatives of general formula I, 
in which
Y1 and Y2, independently of one another, each mean a hydrogen atom or a group xe2x80x94C(O)R5,
and Y3 means a hydrogen atom or a hydroxy group, a halogen atom, a group xe2x80x94OC(O)R5 or an xe2x80x94OR5 group, whereby
R5 stands for an aromatic radical with 5 to 12 C atoms or for an aliphatic, straight-chain or branched, saturated or unsaturated C1-C12 alkyl radical, which optionally is interrupted by 1-2 oxygen atoms, 1-2 sulfur atoms and/or 1-2 NH groups and/or optionally is substituted by 1-2 hydroxy groups, 1-2 amino groups, 1-2 SH groups, 1-2 COOH groups and/or 1-2 phenyl groups,
and the group Y3 can be present both in the 2xcex1-situation and the epimeric 2xcex2-situation,
R1 and R2 each mean a hydrogen atom or together an exocyclic methylene group,
R3 and R4, independently of one another, mean a hydrogen atom, a fluorine, chlorine or bromine atom, an alkyl group with 1 to 4 carbon atoms, together a methylene group or together with quaternary carbon atom 20 a 3- to 7-membered, saturated or unsaturated carbocyclic ring,
Q means a straight-chain alkylene group with 1 to 5 carbon atoms,
X1 and X2 together mean a double-bound keto-oxygen atom or, independently of one another, a hydrogen atom, a hydroxy group, an xe2x80x94OC(O)R5 group, a fluorine, chlorine or bromine atom, whereby X1 and X2, not at the same time, each should be a hydroxy group or each an xe2x80x94OC(O)R5 group,
Z means a carbocyclic or heterocyclic, optionally aromatic or heteroaromatic ring with 5 or 6 ring members or a condensed ring system that consists of a 5- and a 6-membered ring or two 6-membered rings, which can be substituted by one or more fluorine, chlorine, bromine or iodine atoms, one or more hydroxy groups, one or more COOR6 groups, one or more C1-C5 alkyl groups, which in turn can be substituted by one or more fluorine, chlorine, bromine or iodine atoms, C1-C6 alkoxy groups and/or COOR6 groups, whereby
R6 stands for a C1-C6 alkyl group, a benzyl group or a phenyl group,
and all possible epimers or diastereomers and mixtures thereof.
The invention also relates to a process for the production of the compounds according to the invention, intermediate products in the production process as well as the use of the compounds according to the invention for the production of pharmaceutical agents.
Especially advantageous embodiments of the invention are the subject of the subclaims.
The group xe2x80x94C(O)R5, which is defined for Y1 and Y2, can carry 1 to 13 carbon atoms and is derived especially from saturated carboxylic acids. The radicals can be cyclic, acyclic, straight-chain or branched, saturated or unsaturated, carbocyclic or heterocyclic. The radicals are preferably derived from C1-C9 carboxylic acids. For example, formic acid, acetic acid, propionic acid, butanoic acid, pentanoic acid and pivalic acid can be mentioned. The groups Y1 and Y2, independently of one another, especially preferably can each mean a hydrogen atom or an acetyl, propionyl or pivaloyl group.
This explanation is also used for the group xe2x80x94OC(O)R5, which is defined for the radicals Y3, X1 and X2.
The group Y3 can mean a hydrogen atom, a fluorine, chlorine or bromine atom or a hydroxy group, an OR5 group or an xe2x80x94OC(O)R5 group.
The alkoxy group Y3 can mean straight-chain or branched, preferably unsubstituted and without interruption of heteroatoms, e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy. The preferred chain length is C1-C9.
Groups R3 and R4, independently of one another, can each mean a fluorine, chlorine or bromine atom, an alkyl group with 1 to 4 carbon atoms (methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl), together a methylene group or together with quaternary carbon atom 20 a 3- to 7-membered, saturated or unsaturated carbocyclic ring.
For R3 and R4, the following preferred combinations apply: R3=H, R4=methyl or R3=methyl, R4=H; R3=R4=methyl; R3 and R4 together form a methylene group or together with tertiary carbon atom 20 form a cyclopropyl ring.
Optional radical R5 from the radical xe2x80x94OC(O)R5 that is defined for Y3, X1 and X2 is an organic radical with 1 to 12 C atoms, which are derived from longer carboxylic acids corresponding to a carbon atom. These radicals can be saturated or unsaturated, branched or unbranched, saturated or unsaturated, acyclic, carbocyclic or heterocyclic. Examples of radicals R5 are methyl, ethyl, propyl, i-propyl, butyl or phenyl groups. The radicals of naturally occurring amino acids are also possible, however.
Preferred radical R5 is derived from C1 to C9, especially C2 to C5 alkanecarboxylic acids, such as, for example, acetic acid, propionic acid, butyric acid or pivaloyl acid. Among the aromatic groups, the phenyl group and substituted phenyl groups are preferred.
Alkyl group R6 can be straight-chain or branched, saturated or unsaturated, and it can mean, e.g., methyl, ethyl, propyl, butyl, isobutyl tert-butyl, pentyl, isopentyl, neopentyl or hexyl.
The benzyl group and the phenyl group R6 can be unsubstituted or else substituted by one or more halogen atom(s), hydroxy group(s), C1-C4 alkoxy group(s), CF3 group(s) or amino group(s). The unsubstituted benzyl and phenyl groups are preferred.
Q is preferably to mean a methylene, ethylene or propylene group.
X1 and X2 preferably together are to mean a carbonyl group
or X1 means a hydroxyl group or a fluorine atom and X2 means a hydrogen atom
or X1 means a hydrogen atom and X2 means a hydroxyl group or a fluorine atom
or X1 means an xe2x80x94OC(O)R6 group and X2 means a hydrogen atom
or X1 means a hydrogen atom and X2 means an xe2x80x94OC(O)R6 group.
The two cases in which X1xe2x95x90X2xe2x95x90OH or X1xe2x95x90X2xe2x95x90Oxe2x80x94C(O)R6 were ruled out, since they are not chemically useful.
Z is preferably to mean a phenyl ring, which is substituted in ortho-, meta- or para-position with one or more methoxy, ethoxy, propoxy, hydroxy, fluorine, chlorine, bromine, methyl, ethyl, propyl or trifluoromethyl groups or Z is preferably to mean a heterocyclic system, such as, e.g., a furan, thiophene, pyrazole, pyrrole, oxazole, thiazole, imidazole ring, which can carry one or more methyl, ethyl or propyl groups at any position(s),.which in turn can be substituted by halogen of the hydroxy groups and can be linked with the initial system via any C-atom, or Z is preferably to mean a heterocyclic condensed system, such as, e.g., a benzofuran, benzothiophene, benzimidazole, benzoxazole, benzothiazole, indole system, which can carry methyl, ethyl or propyl groups at any position, which in turn can be substituted by halogen of the hydroxy groups and can be linked with the initial system via any C-atom.
If the term halogen is used, fluorine, chlorine, bromine or iodine in connection with substitution patterns of radicals and preferably bromine or iodine as leaving groups in the process are meant.
Of the compounds of general formula I according to the invention, the following compounds are quite especially preferred:
(7E)-(1R,3R,24aR)-24a-(Oxazol-4-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol
(7E)-(1R,3R,24aS)-24a-(oxazol-4-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol
(5Z,7E)-(1S,3R,24aR)-24a-(oxazol-4-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol
(5Z,7E)-(1S,3R,24aS)-24a-(oxazol-4-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol
(7E)-(1R,3R,24aR)-24a-(thiazol-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol
(7E)-(1R,3R,24aS)-24a-(thiazol-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol
(7E)-(1R,3R)-1,3-dihydroxy-24a-(thiazol-2-yl-)-24-a-homo-19-nor-9,10-secochola-5,7-dien-24a-one
(5Z,7E)-(1S,3R,24aR)-24a-(thiazol-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol
(5Z,7E)-(1S,3R,24aS)-24a-(thiazol-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol
(5Z,7E)-(1S,3R)-1,3-dihydroxy-24a-(thiazol-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-trien-24a-one
(7E)-(1R,3R,24aR)-24a-(4-methylthiazol-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol
(7E)-(1R,3R,24aS)-24a-(4-methylthiazol-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol
(7E)-(1R,3R)-1,3-dihydroxy-24a-(4-methylthiazol-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-one
(5Z,7E)-(1S,3R,24aR)-24a-(4-methylthiazol-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol
(5Z,7E)-(1S,3R,24aS)-24a-(4-methylthiazol-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol
(5Z,7E)-(1S,3R)-1,3-dihydroxy-24a-(4-methylthiazol-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-trien-24a-one
(7E)-(1R,3R,24aR)-24a-(thien-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol
(7E)-(1R,3R,24aS)-24a-(thien-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol
(7E)-(1R,3R)-1,3-dihydroxy-24a-(thien-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-one
(5Z,7E)-(1S,3R,24aR)-24a-(thien-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol
(5Z,7E)-(1S,3R,24aS)-24a-(thien-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol
(7E)-(1R,2S,3R,24aR)-24a-thien-2-yl-24a-homo-19-nor-9,10-secochola-5,7-diene-1,2,3,24-tetrol
(7E)-(1R,2S,3R,24aS)-24a-thien-2-yl-24a-homo-19-nor-9,10-secochola-5,7-diene-1,2,3,24-tetrol
(7E)-(1R,2S,3R)-24a-thien-2-yl-1,2,3-trihydroxy-24a-homo-9,10-secochola-5,7-dien-24a-one
(7E)-(1R,3R,24aR)-24a-(4-methylthien-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol
(7E)-(1R,3R,24aS)-24a-(4-methylthien-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol
(7E)-(1R,3R)-1,3-dihydroxy-24a-(4-methylthien-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-one
(5Z,7E)-(1S,3R,24aR)-24a-(4-methylthien-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol
(5Z,7E)-(1S,3R,24aS)-24a-(4-methylthien-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol
(5Z,7E)-(1S,3R)-1,3-dihydroxy-24a-(4-methylthien-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-trien-24a-one
(7E)-(1R,2S,3R,24aR)-24a-(4-methylthien-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,2,3,24-tetrol
(7E)-(1R,2S,3R,24aS)-24a-(4-methylthien-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,2,3,24-tetrol
(7E)-(1R,2S,3R)-24a-(4-methylthien-2-yl)-1,2,3-trihydroxy-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-one
(7E)-(1R,3R,24aR)-24a-(5-ethylthien-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol
(7E)-(1R,3R,24aS)-24a-(5-ethylthien-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol
(7E)-(1R,3R,24aR)-24a-[5-(2-hydroxyethyl)-4-methylthiazol-2-yl]-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol
(7E)-(1R,3R,24as)-24a-[5-(2-hydroxyethyl)-4-methylthiazol-2-yl]-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol
(7E)-(1R,3R)-1,3-dihydroxy-24a-[5-(2-hydroxyethyl)-4-methylthiazol-2-yl]-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-one
(7E)-(1R,3R,24aR)-24a-(benzothiazol-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol
(7E)-(1R,3R,24aS)-24a-(benzothiazol-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol
(7E)-(1R,3R)-24a-(benzothiazol-2-yl)-1,3-dihydroxy-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-one
(7E)-(1R,3R,24aR)-24a-(benzofuran-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol
(7E)-(1R,3R,24aS)-24a-(benzofuran-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol
(7E)-(1R,3R)-24a-(benzofuran-2-yl)-1,3-dihydroxy-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-one
(7E)-(1R,3R,24aR)-24a-(benzothiophen-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol
(7E)-(1R,3R,24aS)-24a-(benzothiophen-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol
(7E)-(1R,3R)-24a-(benzothiophen-2-yl)-1,3-dihydroxy-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-one
(7E)-(1R,3R,24aR)-24a-(1-methylbenzimidazol-2-yl)-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol
(7E)-(1R,3R,24aS)-24a-(1-methylbenzimidazol-2-yl)-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol
(7E)-(1R,3R)-1,3-dihydroxy-24a-(1-methylbenzimidazol-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-one
(7E)-(1R,3R)-1-(1,3-dihydroxy-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-yl)-3-[(4-methoxyphenyl)-methoxy]-1H-pyrazole-4-carboxylic acid ethyl ester
(7E)-(1R,3R)-1-(1,3-dihydroxy-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-yl)-3-hydroxy-1H-pyrazole-4-carboxylic acid ethyl ester
(7E)-(1R,3R,24aR)-24a-(4-methylphenyl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol
(7E)-(1R,3R,24aS)-24a-(4-methylphenyl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol
(7E)-(1R,3R)-1,3-dihydroxy-24a-(4-methylphenyl)-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-one
(7E)-(1R,2R,3R,24aR)-24a-(4-methylphenyl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,2,3,24a-tetrol
(7E)-(1R,RS,3R,24aS)-24a-(4-methylphenyl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,2,3,24a-tetrol
(7E)-(1R,3R,24aR)-24a-(4-trifluoromethylphenyl)-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol
(7E)-(1R,3R,24aS)-24a-(4-trifluoromethylphenyl)-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol
(7E)-(1R,3R)-1,3-dihydroxy-24a-(4-trifluoromethylphenyl)-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-one
(7E)-(1R,3R,24aR)-24a-(4-methoxyphenyl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol
(7E)-(1R,3R,24aS)-24a-(4-methoxyphenyl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol
(7E)-(1R,3R)-1,3-dihydroxy-24a-(4-methoxyphenyl)-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-one
(7E)-(1R,3R,20S,24aR)-24a-(thiazol-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol
(7E)-(1R,3R,20S,24aS)-24a-(thiazol-2-yl)-24-a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol
(7E)-(1R,3R,20S)-1,3-dihydroxy-24a-(thiazol-2-yl)-24-a-homo-19-nor-9,10-secochola-5,7-dien-24a-one
(5Z,7E)-(1S,3R,20S,24aR)-24a-(thiazol-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol
(5Z,7E)-(1S,3R,20S,24aS)-24a-(thiazol-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol
(5Z,7E)-(1S,3R,20S)-1,3-dihydroxy-24a-(thiazol-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-trien-24a-one
(5Z,7E)-(1S,3R,24S)-24-(thiazol-2-yl)-9,10-secochola-5,7,10(19)-triene-1,3,24-triol
(5Z,7E)-(1S,3R,24R)-24-(thiazol-2-yl)-9,10-secochola-5,7,10(19)-triene-1,3,24-triol
(5Z,7E)-(1S,3R)-1,3-dihydroxy-24-(thiazol-2-yl)-9,10-secochola-5,7,10(19)-trien-24-one
(7E)-(1R,3R,20S,24aR)-24a-(oxazol-4-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol
(7E)-(1R,3R,20S,24aS)-24a-(oxazol-4-yl)-24-a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol
(7E)-(1R,3R,20S)-1,3-dihydroxy-24a-(oxazol-4-yl)-24-a-homo-19-nor-9,10-secochola-5,7-dien-24a-one
(5Z,7E)-(1S,3R,20S,24aR)-24a-(oxazol-4-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol
(5Z,7E)-(1S,3R,20S,24aS)-24a-(oxazol-4-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol
(5Z,7E)-(1S,3R,20S)-1,3-dihydroxy-24a-(oxazol-4-yl)-24a-homo-9,10-secochola-5,7,10(19)-trien-24a-one
(5Z,7E)-(1S,3R,24R)-24-(oxazol-4-yl)-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol
(5Z,7E)-(1S,3R,24S)-24-(oxazol-4-yl)-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol
(5Z,7E)-(1S,3R)-1,3-dihydroxy-24-(oxazol-4-yl)-9,10-secochola-5,7,10(19)-trien-24-one
(7E)-(1R,3R,20S,24aR)-24a-(4-methylthiazol-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol
(7E)-(1R,3R,20S,24aS)-24a-(4-methylthiazol-2-yl)-24-a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol
(7E)-(1R,3R,20S)-1,3-dihydroxy-24a-(4-methylthiazol-2-yl)-24-a-homo-19-nor-9,10-secochola-5,7-dien-24a-one
(5Z,7E)-(1S,3R,20S,24aR)-24a-(4-methylthiazol-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol
(5Z,7E)-(1S,3R,20S,24aS)-24a-(4-methylthiazol-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol
(5Z,7E)-(1S,3R,20S)-1,3-dihydroxy-24a-(4-methylthiazol-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-trien-24a-one
(5Z,7E)-(1S,3R,24R)-24-(4-methylthiazol-2-yl)-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol
(5Z,7E)-(1S,3R,24S)-24-(4-methylthiazol-2-yl)-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol
(5Z,7E)-(1S,3R)-1,3-dihydroxy-24-(4-methylthiazol-2-yl)-9,10-secochola-5,7,10(19)-trien-24-one
(7E)-(1R,3R,20S,24aR)-24a-(4-methylthien-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol
(7E)-(1R,3R,20S,24aS)-24a-(4-methylthien-2-yl)-24-a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol
(7E)-(1R,3R,20S)-1,3-dihydroxy-24a-(4-methylthien-2-yl)-24-a-homo-19-nor-9,10-secochola-5,7-dien-24a-one
(5Z,7E)-(1S,3R,20S,24aR)-24a-(4-methylthien-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol
(5Z,7E)-(1S,3R,20S,24aS)-24a-(4-methylthien-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol
(5Z,7E)-(1S,3R,20S)-1,3-dihydroxy-24a-(4-methylthien-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-trien-24a-one
(5Z,7E)-(1S,3R,24R)-24-(4-methylthien-2-yl)-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol
(5Z,7E)-(1S,3R,24S)-24-(4-methylthien-2-yl)-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol
(5Z,7E)-(1S,3R)-1,3-dihydroxy-24-(4-methylthien-2-yl)-9,10-secochola-5,7,10(19)-trien-24-one
(7E)-(1R,3R,20S,24aR)-24a-(thien-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol
(7E)-(1R,3R,20S,24aS)-24a-(thien-2-yl)-24-a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol
(7E)-(1R,3R,20S)-1,3-dihydroxy-24a-(thien-2-yl)-24-a-homo-19-nor-9,10-secochola-5,7-dien-24a-one
(5Z,7E)-(1S,3R,20S,24aR)-24a-(thien-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol
(5Z,7E)-(1S,3R,20S,24aS)-24a-(thien-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol
(5Z,7E)-(1S,3R,20S)-1,3-dihydroxy-24a-(thien-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-trien-24a-one
(5Z,7E)-(1S,3R,24R)-24-(thien-2-yl)-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol
(5Z,7E)-(1S,3R,24S)-24-(thien-2-yl)-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol
(5Z,7E)-(1S,3R)-1,3-dihydroxy-24-(thien-2-yl)-9,10-secochola-5,7,10(19)-trien-24-one
(5Z,7E)-(1S,3R,24S)-24-(4-methylthiazol-2-yl)-9,10-secochola-5,7,10(19)-triene-1,3,24-triol
(5Z,7E)-(1S,3R,24R)-24-(4-methylthiazol-2-yl)-9,10-secochola-5,7,10(19)-triene-1,3,24-triol
(5Z,7E)-(1S,3R)-1,3-dihydroxy-24-(4-methylthiazol-2-yl)-9,10-secochola-5,7,10(19)-trien-24-one
(5Z,7E)-(1S,3R,24S)-24-(thien-2-yl-)-9,10-secochola-5,7,10(19)-triene-1,3,24-triol
(5Z,7E)-(1S,3R,24R)-24-(thien-2-yl)-9,10-secochola-5,7,10(19)-triene-1,3,24-triol
(5Z,7E)-(1S,3R)-1,3-dihydroxy-24-(thien-2-yl)-9,10-secochola-5,7,10(19)-trien-24-one
(5Z,7E)-(1S,3R,24S)-24-(4-methylthien-2-yl)-9,10-secochola-5,7,10(19)-triene-1,3,24-triol
(5Z,7E)-(1S,3R,24R)-24-(4-methylthien-2-yl)-9,10-secochola-5,7,10(19)-triene-1,3,24-triol
(5Z,7E)-(1S,3R)-1,3-dihydroxy-24-(4-methylthien-2-yl)-9,10-secochola-5,7,10(19)-trien-24-one
(7E)-(1R,3R,24aR)-24a-fluoro-24a-(thiazol-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3-diol
(7E)-(1R,3R,24aS)-24a-fluoro-24a-(thiazol-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3-diol
(5Z,7E)-(1S,3R,24aR)-24a-fluoro-24a-(thiazol-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene-1,3-diol
(5Z,7E)-(1S,3R,24aS)-24a-fluoro-24a-(thiazol-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene-1,3-diol
(7E)-(1R,3R,24aR)-24a-(acetyloxy)-24a-(thiazol-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol
(7E)-(1R,3R,24aS)-24a-(acetyloxy)-24a-(thiazol-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol
(7E)-(1R,3R,24aR)-24a-(2,2-dimethylpropanoyloxy)-24a-(thiazol-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol
(7E)-(1R,3R,24aS)-24a-(2,2-dimethylpropanoyloxy)-24a-(thiazol-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol
(7E)-(1R,3R)-2-bromo-24a-(thiazol-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol.
The substances according to the invention have a considerably higher metabolic stability than the structurally related compounds of the prior art and are therefore suitable in a special way for systemic administrations.
Relative to the structurally related compounds of the prior art, some of the substances according to the invention are also characterized in that they show a stronger action on cell differentiation, whereby the action on the calcium balance does not increase.
Others of the substances according to the invention, however, exhibit an antagonistic or partial agonistic profile of action, which makes possible new uses.
Determination of Biological Activity
The vitamin D activity of the substances according to the invention is determined with the aid of the calcitriol-receptor test. It is carried out using a protein extract from the intestines of juvenile pigs. Receptor-containing protein extract is incubated in a test tube with 3H-calcitriol (5xc3x9710xe2x88x9210 mol/l) in a reaction volume of 0.27 ml in the absence and in the presence of test substances for two hours at 4xc2x0 C. To separate free and receptor-bound calcitriol, a charcoal-dextran absorption is carried out. To this end, 250 xcexcl of a charcoal-dextran suspension is fed to each test tube and incubated at 4xc2x0 C. for 20 minutes. Then, the samples are centrifuged at 10,000 g for 5 minutes at 40xc2x0 C. The supernatant is decanted and measured in a xcex2-counter after 1 hour of equilibration in Picofluor 15(trademark).
The competition curves that are obtained at various concentrations of test substance as well as of reference substance (unlabeled calcitriol) at constant concentration of the reference substance (3H-calcitriol) are placed in relation to one another, and a competition factor (KF) is determined.
It is defined as a quotient of the concentrations of the respective test substance and the reference substance, which are necessary for 50% competition:
KF=Concentration of test substance at 50% competition/Concentration of reference substance at 50% competition
To determine the acute hypercalcemic action of various calcitriol derivatives, the test that is described below is carried out:
The action of control (solution base), reference substance (1,25-dihydroxy vitamin D3=calcitriol) and test substance is tested in each case after one-time subcutaneous administration in groups of 10 healthy male rats (140-170 g). During the testing time, the rats are kept in special cages to determine the excretion-of water-and mineral substances. Urine is collected in 2 fractions (0-16 hours and 16-22 hours). An oral dose of calcium (0.1 mmol of calcium in 6.5% alpha-hydroxypropyl-cellulose, 5 ml/animal) replaces at 1600 hours the calcium intake that is lacking by food deprivation. At the end of the test, the animals are killed by decapitation and exsanguinated to determine the serum-calcium values. For the primary screen test in vivo, an individual standard dose (200 xcexcg/kg) is tested. For selected substances, the result is supported by establishing a dose-effect relation.
A hypercalcemic action is shown in serum-calcium level values that are higher than in the control.
The significance of differences occurring between substance groups and controls and between test substance and reference substance are supported with suitable statistical processes. The result is indicated as dose ratio DR (DR=factor of test substance dose/reference substance dose for comparable actions).
The differentiation-stimulating action of calcitriol analogues is also detected quantitatively.
It is known in the literature [D. J. Mangelsdorf et al., J. Cell. Biol. 98: 391 (1984)] that the treatment of human leukemia cells (promyelocyte cell line HL 60) in vitro with calcitriol induces the differentiation of cells to macrophages.
HL 60 cells are cultivated in tissue culture medium (RPMI 10% fetal calf serum) at 37xc2x0 C. in an atmosphere of 5% CO2 in air.
For substance testing, the cells are centrifuged off, and 2.0xc3x97105 cells/ml in phenol red-free tissue culture medium is taken up. The test substances are dissolved in ethanol and diluted with tissue culture medium without phenol red to the desired concentration. The dilution stages are mixed with the cell suspension at a ratio of 1:10, and 100 xcexcl each of this cell suspension that is mixed with substance is pipetted into an indentation of a 96-hole plate. For control, a cell suspension is mixed analogously with the solvent.
After incubation for 96 hours at 37xc2x0 C. in 5% CO2 in air, 100 xcexcl of an NBT-TPA solution (nitro blue tetrazolium (NBT), final concentration in the batch of 1 mg/ml, tetradecanoyl phorbolmyristate-13-acetate (TPA), final concentration in the batch of 2xc3x9710xe2x88x927 mol/l) is pipetted into each indentation of the 96-hole plate in the cell suspension.
By incubation for 2 hours at 37xc2x0 C. and 5% CO2 in air, NBT is reduced to insoluble formazan because of the intracellular oxygen radical release, stimulated by TPA, in the cells that are differentiated to macrophages.
To complete the reaction, the indentations of the 96-hole plate are suctioned off, and the cells are affixed to the bottom of the plate by adding methanol and dried after affixing. To dissolve the intracellular formazan crystals that are formed, 100 xcexcl of potassium hydroxide (2 mol/l) and 100 xcexcl of dimethyl sulfoxide are pipetted into each indentation and ultrasonically treated for 1 minute. The concentration of formazan is measured by spectrophotometry at 650 nm.
As a yardstick for the differentiation induction of HL 60 cells to macrophages, the concentration of formed formazan applies. The result is indicated as a dose ratio (DR=factor of test substance dose/reference substance dose for comparable semi-maximum actions).
The results of the calcitriol-receptor test and the determination of the dose ratio of the differentiation induction of HL 60 cells and the dose ratio for hypercalcemia are summarized below:
Examples of test substances:
(7E)-(1R,3R,2aR)-24a-(Oxazol-4-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol 16a
(5Z,7E)-(1S,3R,24aR)-24a-(oxazol-4-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol 20a
(7E)-(1R,3R,24aS)-24a-(thien-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol 55b
(7E)-(1R,3R)-1,3-dihydroxy-24a-(thien-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-one 57
(5Z,7E)-(1S,3R,24R)-24-(thiazol-2-yl)-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol 217a
In addition to a considerable affinity to the vitamin D receptor, the compounds listed show a pronounced cell-differentiating activity.
The induction of a hypercalcemia is carried out, however, only at very much higher doses than in the case of calcitriol.
By the reduced property of triggering a hypercalcemia as well as the high metabolic stability, the substances according to the invention are suitable in a special way for the production of pharmaceutical agents for the treatment of diseases that are characterized by hyperproliferation and deficient cell differentiation. Included in these are, for example, hyperproliferative diseases of the skin (psoriasis, pityriasis subia pilasis, acne, ichthyosis) and pruritus, as well as tumor diseases and precancerous stages (for example, tumors of the intestines, carcinomas of the breast, lung tumors, prostate carcinomas, leukemias, T-cell lymphomas, melanomas, Betazell carcinoma, squamous carcinoma, actinic keratoses, cervix dysplasias, and metastasizing tumors of any type).
Also, for the treatment and prophylaxis of diseases that are characterized by a disequilibrium of the immune system, the substances according to the invention are suitable. These include eczemas and diseases of the atopic Formon series and inflammatory diseases (rheumatoid arthritis; respiratory tract diseases, e.g., asthma), as well as auto-immune diseases, such as, for example, multiple sclerosis, diabetes mellitus type I, myasthenia gravis, lupus erythematosus, scleroderma, bullous skin diseases (pemphigus, pemphigoid), further rejection reactions in the case of autologous, allogeneic or xenogeneic transplants, as well as AIDS. In all of these diseases, the new compounds of general formula I can be combined advantageously with other substances that have an immunosuppressive action, such as cyclosporin A, FK 506, rapamycin and anti-CD 4-antibodies.
The substances are also suitable for therapy of secondary hyperparathyroidism and renal osteodystrophia because of the property of calcitriols to drop the parathormone synthesis.
Owing to the presence of the vitamin D receptor in the insulin-producing cells of the pancreas, the substances are suitable by increasing the insulin secretion for the therapy of diabetes mellitus type II.
Further, it has been found, surprisingly enough, that by topical application of the compounds according to the invention on the skin of mice, rats and guinea pigs, an increased reddening of the skin and increase of the thickness of the epidermis can be induced. The increase in the reddening of the skin is determined based on the increase in the red value of the skin surface that can be quantified with a calorimeter. The red value is typically increased 1.5-fold after the substance (dose 0.003%) is administered three times at intervals of 24 hours. The increase in the thickness of the epidermis is quantified in the histological preparation. It is typically increased 2.5-fold. The number of proliferating epidermal cells (cells in the S-phase of the cell cycle) is determined by flow cytometry and is typically increased by a factor of 6.
These properties of the derivatives in the vitamin D series according to the invention can appear suitable for therapeutic use in the case of atrophic skin, as it occurs in natural skin aging because of increased light exposure or medicinally-induced skin atrophy by treatment with glucocorticoids.
Further, it can be assumed that wound healing can be accelerated by topical application with the new compounds.
In cell populations of the hair follicle, which contribute decisively to hair growth or to hair cycle regulation, it was possible to detect vitamin D3 receptor proteins [W. E. Stumpf et al., Cell Tissue Res. 238, 489 (1984); P. Milde et al., J. Invest. Dermatol. 97, 230 (1991)]. In addition, in vitro findings on isolated hair follicle keratinocytes show a proliferation-inhibiting and differentiation-stimulating influence of 1,25-(OH)2-D3.
From clinical observations, it is known that the vitamin D3-resistant rickets often accompanies alopecia, which develops in early infancy. Experimental findings show that the vitamin D3 bonding site of the VDR in this disease mutates, i.e., is defective [K. Kristjansson et al., J. Clin. Invest. 92, 12 (1993)]. Keratinocytes, which were isolated from the hair follicles of these patients, do not react in vitro to the addition of 1,25-(OH)2D3 [S. Arase et al., J. Dermatol. Science 2, 353 (1991)].
These findings indicate a decisive role for 1,25-(OH)2D3 in the regulation of hair growth.
These analogues are therefore especially suitable for the production of pharmaceutical agents for the treatment of diseases which accompany disrupted hair growth (androgenetic alopecia, alopecia areata/totalis, chemotherapy-induced alopecia) or for supporting physiological hair growth without causing the side-effects of calcitriol (especially hypercalcemia).
Senile and postmenopausal osteoporosis is characterized by an increased bone turnover with an overall negative balance. Owing to the bone shrinkage especially of trabecular bones, fractures result to an increased extent. Owing to the stimulating action of calcitriol, both in the number and the conduct of synthesis of cells forming new bones (osteoblasts), the substances according to the invention are suitable for therapy and prophylaxis of senile and postmenopausal osteoporosis (EP 0 634 173 A1), of steroid-induced osteoporosis as well as for accelerated healing of arthroplasties without causing the side-effects of calcitriol (especially hypercalcemia). For the therapy of various forms of osteoporosis, they can be combined advantageously with estradiol or other derivatives of estrogen.
Finally, it was possible to show that calcitriol increases the synthesis of a growth substance for nerve cells (nerve growth factor) [M. S. Saporito et al. Brain Res. 633, 189 (1994)]. The compounds according to the invention are-therefore also suitable for treating degenerative diseases of the peripheral and central nervous system, such as Alzheimer""s disease and amyotrophic lateral sclerosis.
In addition, it has been found that certain compounds of general formula I in HL 60 cells antagonize, surprisingly enough, the action of calcitriol.
Such compounds can be used for the therapy of hypercalcemias, such as, for example, in hypervitaminosis D or intoxication with calcitriol and calcitriol-like active substances, or in the case of increased extrarenal calcitriol synthesis in granulomatous diseases (sarcoidosis, tuberculosis). Also, paraneoplastic hypercalcemias (for example, in osteolytic metastases and tumors with increased synthesis of parathormone-related peptides) as well as in hypercalcemias in the case of hyperparathyroidism.
In addition, calcitriol antagonists can be used for birth control. In the reproductive tracts of female and male animals, the vitamin D receptor is expressed. It is known that the female and male fertility of vitamin-D-deficient animals is reduced. By short-term substitution of calcitriol, the reproductive output can be increased. Calcitriol antagonists are therefore able to influence female and male fertility.
Since calcitriol, under certain conditions, shows an immunosuppressive action, calcitriol receptor antagonists can also be used as immunostimulants, e.g., in the case of weak defenses against infections, AIDS.
Calcitriol is known to be able to modulate hair growth. Calcitriol antagonists can therefore be used therapeutically in the case of undesirable hair growth, e.g., in hirsutism.
Vitamin D has long been known to play a stimulating role in the formation of arteriosclerotic plaque. In such vascular lesions, a calcitriol-regulated protein, osteopontin, is found to be increased, to which a role in vascular sclerosis is attributed [R. Eisenstein et al. Arch. Path. 77, 27 (1964), L. A. Fitzpatrick et al., J. Clin. Invest. 94, 1597 (1994)]. Calcitriol antagonists are therefore suitable for therapy and prophylaxis of all types of arteriosclerosis.
Finally, calcitriol antagonists are suitable because of the property of calcitriol to increase unspecific immune reactions of monocytic cells, for therapy of inflammatory diseases, especially of a chronic nature, such as rheumatoid arthritis, Crohn""s disease, ulcerative colitis, and granulomatous diseases such as sarcoidosis and other foreign-body reactions.
For all listed therapeutic applications, it is true that the compounds according to the invention are able to achieve a therapeutic action in the above-mentioned clinical pictures without causing the side-effects of calcitriol (especially hypercalcemia).
This invention thus relates to pharmaceutical preparations that contain at least one compound according to general formula I together with a pharmaceutically compatible vehicle.
The compounds can be formulated as solutions in pharmaceutically compatible solvents or as emulsions, suspensions or dispersions in suitable pharmaceutical solvents or vehicles or as pills, tablets or capsules, which contain solid vehicles in a way known in the art.
For topical use, the compounds are advantageously formulated as creams or ointments or in a similar form of pharmaceutical agent that is suitable for topical use. Each such formulation can also contain other pharmaceutically compatible and nontoxic adjuvants, such as, e.g., stabilizers, antioxidants, binders, dyes, emulsifiers or flavoring additives.
The compounds are advantageously administered by injection, intravenous infusion of suitable sterile solutions, as an aerosol via bronchial tubes and lungs, or as oral dosage via the alimentary tract or topically in the form of creams, ointments, lotions or suitable transdermal patches, as is described in EP-A 0 387 077.
The daily dose is
approximately 0.1 xcexcg/patient/dayxe2x80x941000 xcexcg/patient/day,
preferably 1.0 xcexcg/patient/dayxe2x80x94500 xcexcg/patient/day.
Process for the Production of the Compounds According to the Invention
The production of the vitamin D derivatives of general formula I is carried out according to the invention from a compound of general formula II, 
in which Yxe2x80x21 and Yxe2x80x22 mean hydroxy protective groups, and Yxe2x80x23 is a hydrogen atom, a halogen atom or a protected hydroxy group.
Xxe2x80x21, Xxe2x80x21 and Zxe2x80x2 are distinguished from X1, X2 and Z in that optionally present hydroxy groups or keto groups can be present in protected form.
The protective groups are preferably alkyl-, aryl- or mixed alkylaryl-substituted silyl groups, e.g., the trimethylsilyl (TMS), triethylsilyl (TES), tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS) or triisopropylsilyl (TIPS) groups or another standard hydroxy protective group (trimethylsilylethoxymethyl, methoxymethyl, methoxyethoxymethyl, ethoxyethyl, tetrahydrofuranyl and tetrahydropyranyl groups) as well as acetyl, propionyl or pivaloyl groups; for the keto groups, these are preferably ketals (1,3-dioxolans, 1,3-dioxanes, dialkoxyketals) (see T. W. Greene, P. G. M. Wuts xe2x80x9cProtective Groups in organic Synthesis,xe2x80x9d 2nd Edition, John Wiley and Sons, 1991).
By simultaneous or successive cleavage of the hydroxy and keto protective groups and optionally by partial, successive or complete esterification of the free hydroxyl groups, the compound of general formula II is converted into a compound of general formula I.
In the case of the silyl protective groups or the trimethylsilylethoxymethyl group, tetrabutylammonium fluoride, hydrofluoric acid or hydrofluoric acid/pyridine or acidic ion exchanger is used for their cleavage. In the case of the ether groups (methoxymethyl, methoxyethoxymethyl, ethoxyethyl, tetrahydropyranyl ether) and ketals, the latter are cleaved off under catalytic action of acid, for example, p-toluenesulfonic acid, pyridinium-p-toluenesulfonate, acetic acid, hydrochloric acid, phosphoric acid or an acidic ion exchanger. Ester groups, however, are hydrolyzed in a basic medium (sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide in water, ethanol, methanol or mixtures of these solvents).
The esterification of the free hydroxy groups can be carried out, if desired, according to standard processes with the corresponding carboxylic acid chlorides, -bromides or -anhydrides.
The production of the starting compounds for general formula II, in which Q means at least one ethylene group, starts from various starting compounds depending on the ultimately desired substitution pattern in 20-position. For the compounds with natural configuration at C-20, the known CD-fragment III is used as starting material [H. H. Inhoffen, G. Quinkert, S. Schxc3xctz, G. Friedrich, E. Tober Chem. Ber. 91, 781-791 (1958)]. 
By introduction of a protective group, the compound of general formula IV 
is obtained, whereby Y4, i.a., can mean a trialkyl-substituted or a mixed arylalkyl-substituted silyl group or a tetrapyranyl or tetrafuranyl group. Ozonolytic cleavage of the side-chain double bond followed by reductive working-up (e.g., sodium borohydride) yields the compound of general formula V. 
The free hydroxy group can now be converted into a leaving group, whereby the compound of general formula VI is produced, 
for which the following is true: L stands for any leaving group, especially for a halogen atom (fluorine, chlorine, bromine, iodine) or a mesylate, tosylate, triflate or nonaflate.
Via the propargyl alcohol VII and the conversion into alcohol VIII and oxidation to aldehyde IX described below, the compound of formula VI opens up a new, not yet known access to ketone XIII further described below that represents an important starting material for the synthesis of vitamin D derivatives according to De Luca [H. F. DeLuca et al. Tetrahedron Lett. 32, 7663 (1991); H. F. DeLuca et al. J. Med. Chem. 37, 3730 (1994)].
This invention thus also relates to a process for the production of ketone XIII via the new intermediate stages of Formulas VII, VIII and IX. The synthesis method can be modified in any way desired for another chain length, by a corresponding protected alkinol being used. By way of example, the synthesis method for a compound in which Q means an ethylene group is described below.
Reaction of the compound of general formula VI with a protected propargyl alcohol, which was previously deprotonated with a base (e.g., sodium hydride, potassium hydride, butyllithium, sodium amide), yields the compound of general formula VII 
for which the following is true: Y5 is to represent a tetrahydropyranyl group, a benzyl group or a used protective group. Hydrogenation of the triple bond and the benzyl ether or optionally followed by cleavage of the tetrahydropyranyl ether under the action of acid (p-toluenesulfonic acid, pyridinium-p-toluenesulfonate, acetic acid, dimethyl aluminum chloride, methylaluminum dichloride, etc.) now produces the compound of general formula VIII, whose free hydroxy group is converted with an oxidizing agent (pyridinium chlorochromate, pyridinium dichromate, Swern conditions, Collins conditions) into the aldehyde of general formula IX. 
By reaction with any nucleophile Nu, which can be brought to reaction with the aldehyde, such as, e.g., anions, optionally organic radicals that contain oxygen or sulfur atoms, optionally substituted Grignard reagents that are optionally protected on sensitive functional groups, or lithium compounds, which can be produced according to methods that are known in the literature, a compound of general formula Xa is obtained as a mixture of-the diastereomeric alcohols. 
For the synthesis of the compounds according to the invention, the compound of general formula X 
is obtained by reaction with a nucleophilic form of Z with the designation Zxe2x80x2, preferably with a metalated aromatic or heteroaromatic compound.
Z can be any of the radicals that are defined for Z, preferably furan, thiophene, oxazole, thiazole, imidazole, pyrazole, pyrrole, benzofuran, benzothiophene, benzoxazole, benzothiazole, benzimidazole, indole or phenyl, whereby the rings can carry one or more substituents at any positions. As substituents, there are fluorine, chlorine, bromine or iodine atoms, one or more hydroxy groups, one or more COOR6 groups, one or more C1-C5 alkyl groups, which in turn can be substituted by one or more fluorine, chlorine, bromine or iodine atoms, C1-C6 alkoxy groups and/or COOR6 groups (and R6 is defined as a C1-C6 alkyl group, a benzyl group-or a phenyl group). The aromatic compounds are converted into the metalated derivatives by hydrogen-lithium exchange, orthometalation, halogen-lithium exchange (use of n-butyllithium, s-butyllithium, t-butyllithium, methyllithium) or reaction of halogen compounds with magnesium or zinc. The linkage to the CD-fragment is always carried out in the metalated position with the exception of oxazole rings, which hook on by rearrangement and recycling at the 4-position [G. Boche et al. Chem. Ber./Receuil 130, 1213 (1997)].
Conversion of the free hydroxy group into acetate groupings (Rxe2x80x2=Me), propionate groupings (Rxe2x80x2=Et) or pivalate groupings (Rxe2x80x2=t-Bu) produces compounds of general formula XI, and it is converted into a compound of general formula XII by cleavage of cyclohexanol protective groups Y4. If Y4 means a silyl group, its cleavage can be carried out, e.g., with use of tetrabutylammonium fluoride, hydrogen fluoride, hydrogen fluoride/pyridine complex; however, if Y4 means a tetrahydropyranyl group or a tetrahydrofuranyl group, its cleavage can be completed under acidic conditions. Subsequent oxidation of the free hydroxy group with an oxidizing agent (pyridinium chlorochromate, pyridinium dichromate, Swern conditions, Collins conditions) yields the compound of general formula XIII. 
Reaction of the ketone of general formula XIII with one of the known phosphine oxides XIV, XV or XVI [XIV: M. R. Uskokovic et al. Tetrahedron Lett. 33, 7701 (1992), A. Mourino et al. Tetrahedron Lett. 38, 4713 (1997), XV: H. F. DeLuca et al. Tetrahedron Lett. 32, 7663 (1991), XVI: H. F. DeLuca et al. J. Med. Chem. 37, 3730 (1994)], 
whereby Yxe2x80x21 and Yxe2x80x22 represent alkyl- or mixed arylalkyl-substituted silyl groups (preferably tert-butyldimethylsilyl, tert-butyldiphenylsilyl, trimethylsilyl, triethylsilyl and triisopropylsilyl groups) and Yxe2x80x23 means the corresponding silyloxy grouping, yields the vitamin D systems of general formulas XVII, XVIII and XIX. 
The compounds of general formulas XVII, XVIII and XIX represent special cases of general formula II and are converted into compounds of general formula I as described above.
In particular, the hydroxy group in position C-24 can be released and converted with an oxidizing agent (e.g., pyridinium chlorochromate, pyridinium dichromate, Collins reagent, Swern conditions, manganese dioxide) into the corresponding ketone, which likewise represents a special case of general formula II. The C-24 alcohols or the C-24 ketone can be converted into halides or dihalides under known conditions. The possibility of the reductive removal of the hydroxy, keto or halogen units also exists.
Any manipulations of the functional groups in the side chain can also be completed in earlier stages.
For the production of compounds of general formula II with altered substitution patterns at C-20, the alcohol of general formula V is oxidized to the aldehyde of general formula XX with an oxidizing agent (e.g., pyridinium chlorochromate, pyridinium dichromate, Collins reagent, Swern conditions, Dess-Martin conditions). The latter can be converted as described [DE 42 20 757, 20-epi: M. J. Calverley Bioorg. Med. Chem. Lett. 3, 1845 (1993)] into compounds of general formula XXI, in which R3 and R4 have the already-mentioned meanings. Then, the reduction with a reducing agent (e.g., sodium borohydride, lithium aluminum hydride, diisobutylaluminum hydride) is carried out to alcohol of general formula XXII, which is further reacted as described above. 
For compounds of general formula II, the following is true: Q is a methylene group, and a start is made from known vitamin D-aldehyde XXIII, which can be modified at position 20 as described above (DE 196 19 036). By way of example, the further reaction of aldehyde with natural configuration at C-20 is described. 
With a reducing agent (e.g., sodium borohydride, lithium aluminum hydride, isobutylaluminum hydride), the alcohol of general formula XXIV, which is converted into a leaving group as described above, is obtained, whereby the compound of general formula XXV accumulates. 
Reaction of the compounds of general formula XXV with the acetonitrile that is deprotonated by a base (e.g., lithium diisopropylamide, sodium hexamethyldisilazide, lithium hexamethyl disilazide, potassium hexamethyl disilazide) produces a compound of general formula XXVI, which is converted by reduction with a reducing agent (e.g., diisobutylaluminium hydride) into a compound of general formula XXVII. 
By reaction with the nucleophile of a carbocyclic or heterocyclic compound, preferably a metalated aromatic or heteroaromatic compound, compounds of general formula XXVIII 
as already shown above, which are to be considered as a special case of general formula II, are obtained and are to be converted into compounds of general formula I as described. In particular, the hydroxy group in position C-24 can be converted into the corresponding ketone with an oxidizing agent (e.g., pyridinium chlorochromate, pyridinium dichromate, Collins reagent, Swern conditions, manganese dioxide), which likewise represents a special case of general formula II. The C-24 alcohols or the C-24 ketone can be converted into halides or dihalides under known conditions. The possibility also exists of the reductive removal of hydroxy, keto or halogen units.
If compounds of general formula I are to be generated, for which Y3 is a halogen atom (e.g., fluorine, chlorine or bromine atom), an A-component of general formula XXX, whereby Y3 is to have the above-mentioned meaning, must by synthesized from the cyclohexane derivative XXIX that is known from the literature [J.-L. Montchamp, J. W. Frost J. Am. Chem. soc. 113, 6296 (1991)] by Hanessian reaction. 
Introduction of a protective group for the free hydroxy group produces the compound of general formula XXXI, which is converted in the acid medium as usual into diol XXXII and by subsequent diol cleavage (sodium periodate, periodic acid) into ketone XXXIII, whereby the definitions for Yxe2x80x21 and Y3 were already indicated. 
In building the vitamin D system, a new approach is used for Y3=halogen, which can also be used, however, for all possible substituents for Y3 (also Y3=a hydrogen atom), as well as for other substitution patterns in the A-ring (e.g., instead of OY1 in 1-position, halogen, (CH2)nxe2x80x94OH or (CH2)nxe2x80x94O(CO)R5 with R5=aliphatic C1-C12 alkyl radical, which optionally is interrupted by 1-2 oxygen atoms, 1-2 sulfur atoms and/or 1-2 NH groups and/or optionally is substituted by 1-2 hydroxy groups, 1-2 amino groups, 1-2 SH groups, 1-2 COOH groups and/or 1-2 phenyl groups, with n=0-4 or an aromatic radical with 5 to 12 C atoms), and also any side chains in 17-position with optionally protected existing hydroxy groups and/or keto groups.
The reactions at the ketone of general formula XIII are described here by way of example but are also valid for other side-chain variants:
By Peterson olefination (reaction with trimethylsilylacetic ester in the presence of a base, such as, e.g., n-butyllithium or lithium diisopropylamide), the compound of general formula XXXIV, whose ester group is converted into the alcohol of general formula XXXV by reduction with a reducing agent (e.g., diisobutylaluminum hydride, lithium aluminum hydride) is obtained from ketone XIII. The conversion of the hydroxy group into a diphenylphosphine oxide derivative of general formula XXXVI is carried out according to standard conditions via an allyl halide (chloride, bromide) or an intermediate tosylate or mesylate. 
The linkage with the ketone of general formula XXXIII ultimately produces the vitamin D system of general formula II with the already mentioned definitions for Y3. The conversion into a compound of general formula I is carried out as described previously by cleavage of the protective groups.
The subject of this invention is thus also a new process for the production of vitamin D derivatives of general formula IIa, 
in which
E means any side chain,
R7, R8, independently of one another, mean a hydrogen atom, a methyl group, or together an exocyclic methylene group or a cyclopropyl ring,
Y2 means a hydrogen atom or a group xe2x80x94(CO)R5,
Y3 means a hydrogen atom, a hydroxy group, a halogen atom, a group xe2x80x94O(CO)R5 or an OR5 group, whereby
R5 stands for an aliphatic C1-C12 alkyl radical, which optionally is interrupted by 1-2 oxygen atoms, 1-2 sulfur atoms and/or 1-2 NH groups and/or optionally is substituted by 1-2 hydroxy groups, 1-2 amino groups, 1-2 SH groups, 1-2 COOH groups and/or 1-2 phenyl groups, or for an aromatic radical with 5 to 12 C atoms,
Y5 means a fluorine atom, a (CH2)nxe2x80x94OH group or a (CH2)nxe2x80x94O(CO)R5 group, whereby n=0 to 4,
and optionally present hydroxy groups are optionally present in protected form, which is characterized in that a ketone of general formula XIIIc 
in which
E means any side chain
and optionally existing keto groups and/or hydroxy groups are present in protected form is converted by reaction with trimethylsilylacetic ester in the presence of a base, such as, e.g., n-butyllithium or lithium aluminum hydride or with a suitable Wittig reagent in an aprotic solvent such as toluene, tetrahydrofuran, diethyl ether or dioxane into a compound of general formula XXXIVc 
in which
Y6 means a C1-C6 alkyl group, a benzyl group, or a phenyl group,
the ester group is converted by reaction with a reducing agent such as Dibah, lithium aluminum hydride, diborane or RedAl in hexane, toluene, tetrahydrofuran, diethyl ether or dioxane into the allyl alcohol of general formula XXXVc 
the allyl alcohol is converted in a way that is known in the art into a compound of general formula XXXVc 
in which
L means any leaving group (halogen, mesylate, tosylate, triflate, nonaflate),
which is isolated or optionally produced in situ and immediately further reacted to a Wittig reagent of general formula XXXVIc, 
in which
G means a C1-C10 alkyl group, a C1-C10 alkoxy group, a phenyl radical or a phenoxy radical,
which then is reacted under known conditions with a ketone of general formula XXXIIIc 
in which
Yxe2x80x23 means a hydrogen atom, a halogen atom or a protected hydroxy group, a group xe2x80x94O(CO)R5 or an OR5 group, and Y5, R7 and R8 have the above-indicated meaning,
and if desired, protective groups are cleaved.
The compounds of general formula IIa can be converted into the desired vitamin D derivatives by cleavage of the protective groups as described above.
Especially suitable is the process according to the invention for the production of vitamin D derivatives, in which Y3 means a halogen atom, but it is not limited thereto.
The additives xe2x80x9caxe2x80x9d in the designation of the formulas (e.g., XXXIVa) is to make clear that the meanings of the radicals are basically the same as in the formula without additive xe2x80x9caxe2x80x9d, but sensitive groups are present in protected form.
An alternative method to the synthesis of compounds of general formula II, for which Xxe2x80x21 and Xxe2x80x22 mean hydrogen atoms and Q represents an ethylene group, starts from alcohol of general formula VIII, whose hydroxy group is converted into a leaving group (e.g., chloride, bromide, iodide, tosylate, mesylate) and is reacted with metalated aromatic or heteroaromatic compounds, whereby compounds of general formula XXXVII accumulate, 
and whose further reaction can be carried out analogously to the above-described compounds.